Hydrochloric Acid → cis-Methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

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Reaction Steps

2-(4-Chloro-2-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.49 g, 20.56 mmol) (reference compound 20) was dissolved in methyl THF (250 mL), then di(1H-imidazol-1-yl)methanone (5.00 g, 30.83 mmol) was added. The mixture was stirred at room temperature under nitrogen for 3 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (6.30 g, 37.00 mmol) was suspended in methyl THF (250 mL), then magnesium chloride (3.52 g, 37.00 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 3 h using a large magnetic stirring bar (flask 2). After the 3 h, the contents of flask 1 was transferred into flask 2. The resulting white suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl, then MTBE (50 mL) and water (50 mL) was added. The phases were separated and the organic layer was washed with water, satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated leaving a slightly yellow oil. The product was flashed on Biotage (340 g) with 1 CV 20% EtOAc in heptane followed by a gradient of 20-60% EtOAc in n-heptane (8 CV). The column was conditioned at 20% EtOAc in -n-heptane (1 CV). Trans-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.5 g, 6%) and cis-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.31 g, 29%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.27 (t, 3H), 1.79-1.99 (m, 2H), 2.03-2.21 (m, 1H), 2.23-2.32 (m, 1H), 2.84-2.95 (m, 1H), 3.33-3.51 (m, 3H), 3.62 (s, 3H), 4.12-4.23 (m, 3H), 4.98-5.21 (m, 1H), 6.98-7.24 (m, 3H). MS m/z 386 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22 (t, 3H), 1.57-1.69 (m, 1H), 1.86-2.01 (m, 2H), 2.36-2.62 (m, 2H), 3.07-3.18 (m, 1H), 3.44 (s, 2H), 3.70 (s, 3H), 4.10-4.21 (m, 2H), 4.32 (br, 1H), 5.67 (br, 1H), 7.02-7.14 (m, 3H). MS m/z 386 (M+H)+

Provenance & Evidence